Pathology of acute asthma
Studies of airway inflammation using induced sputum in acute asthma suggest a heterogeneous inflammatory infiltrate with a mixture of neutrophils and eosinophils.8,9 The pattern of this inflammatory infiltrate differs from the allergen induced asthma model. This suggests that the pathogenesis of acute asthma is different from that seen in chronic disease, although it is not clear whether this is a feature of acute disease or the acute trigger. Pathological studies of the most severe acute group—those with status asthmaticus who require mechanical ventilation—have examined bronchoalveolar lavage (BAL) fluid and endobronchial biopsy tissue. Increased numbers of neutrophils are seen in the BAL fluid, with raised levels of eosinophils in the first 48 hours but appearing to fall quickly in response to corticosteroid therapy.10 BAL fluid from a comparable group contained markedly increased levels of the pro‐inflammatory mediators interleukin (IL)‐1β, IL‐6, and tumour necrosis factor (TNF)‐α.11 This intense airway inflammation was present despite the use of very high dose parenteral corticosteroids, implying an inherent resistance in controlling acute airway inflammation not generally seen in stable asthma. While it is possible that these findings are the effect of severe chronic asthma alone and it is this entity that is resistant to treatment with corticosteroids, it is likely that the acute triggers of asthma exacerbations may also directly modify the airway inflammatory phenotype, making it more resistant to treatment.
T cell activation is also a feature of acute severe asthma,12 with increased T cell markers in peripheral blood and increased numbers of activated (CD25+) CD8 cells in the tissue of fatal cases of asthma.13 Oxidant stress is an additional key component of acute asthma. The marked granulocyte influx and activation in acute asthma is accompanied by increased oxygen free radical production which overwhelms host antioxidant defences and results in oxidation of lipids and proteins (fig 33).). Lipid peroxidation, assessed as isoprostane levels, is found to be markedly increased in acute asthma, and falls with resolution of the exacerbation.14
Figure 3 Environmental exposures that trigger asthma exacerbations generate specific cytokine response patterns that result in a granulocyte infiltration, activation, and oxidative stress.
Pathological studies of fatal asthma exacerbations reveal marked hyperinflation due to air trapping from mucus plugging of the airways.15 Additional findings confirm the presence of inflammation that is intense but restricted to the airways, and occurs in association with airway remodelling. Both airway mucus cell hyperplasia and mucus secretion are relevant mechanisms of mucus plugging in asthma. Mucus cell hyperplasia may be mediated by IL‐13 and epidermal growth factor receptor activation.16,17,18 Mediators that can trigger mucus secretion include neutrophil elastase, mast cell chymase, eosinophil cationic protein (ECP), and leukotrienes.18 Many of these mediators are present as part of the airway inflammatory response in acute asthma. Whereas mild asthma and allergen induced asthma are characterised by eosinophilic airway inflammation, in acute severe asthma the intense neutrophilic inflammation demonstrates increased levels of neutrophil elastase, as well as eosinophil degranulation with high levels of ECP.5,8,9 Compared with controls, cases of fatal asthma show increased mucous gland area, increased percentage of degranulated mast cells, and increased numbers of neutrophils in the submucosal glands.15 The mucus plugs in fatal asthma are found to contain mucins, plasma proteins, and inflammatory cells.19
Virus induced acute asthma
An association between acute respiratory virus infection and asthma exacerbations has been observed for some time. The importance of virus infection as an acute trigger was suggested by epidemiological surveys that showed an association between symptomatic colds and acute asthma, while failing to show an association with allergen or fungal spore exposure.20,21 However, confirmation was hampered by insensitive techniques to detect rhinoviruses and coronaviruses. The advent of sensitive polymerase chain reaction detection techniques has confirmed that viral upper respiratory tract infections (URTIs) are an important trigger of acute exacerbations of asthma. In school age children 80–85% of exacerbations are associated with viral URTI.22,23 In adults the rates of virus detection have varied with studies, but they remain the single most prevalent trigger for acute asthma (table 11).). In a large community and hospital based UK study, symptomatic colds were associated with 80% of asthma exacerbations although detection of virus from the upper airway was much lower (44%).24 While this may reflect a difference in virus induced asthma between children and adults, it may also be accounted for in adults by lower shedding of virus from the upper respiratory tract and a delay between acute infection and deterioration of asthma. In contrast, in a hospital based study of severe acute asthma in which polymerase chain reaction for common respiratory viruses was employed using induced sputum, respiratory viruses were detected in 76%5 and, more recently, another study in adults detected respiratory viruses in 78%.25 In both adults and children, the virus most frequently identified with acute asthma exacerbations is rhinovirus (RV). In keeping with this is the strong epidemiological evidence that links asthma exacerbations to the recommencing of school, a recognised feature of RV induced colds.26,27 The questions these studies raise is how respiratory viruses, in particular RV, can induce acute asthma and why asthmatics are so predisposed to the effects of infection.
RVs are single strand RNA viruses belonging to the picornavirus family and are transmitted by direct contact and via the respiratory route with inoculation and replication occurring in the epithelium of the upper airway.28 In vitro models of RV infection of human bronchial epithelial cells (BECs) have been important in aiding our understanding of the mechanisms by which RV infection can induce acute asthma. At first RV was thought to be incapable of infecting the lower airway and its effect on asthma was thought to be indirect. However, detection of RV by bronchoscopy and confirmation of its presence in lower airway BECs in asthmatic subjects confirms that direct infection of the lower airways can occur.29,30 In vitro cell culture models of cell lines derived from airway BECs showed that RV could infect and replicate in them.31,32 This was also found to occur as effectively in primary BECs obtained from the airways and then cultured. In fact, there was no difference in infectivity or viral yields between upper and lower airway epithelial cells.33 However, when epithelial cells were cultured and then differentiated, they were found to be much more resistant to infection with RV and to yield far less virus than undifferentiated primary BECs.34 The implications for asthma may be that a damaged epithelium is more susceptible to infection and therefore the effects of infection on the lower airway are amplified ((tablestables 3 and 44).). This is supported by a recent study which compared the lower airway inflammatory response in patients with acute viral asthma and in non‐asthmatic subjects with RV infection.25 Absolute neutrophil counts from induced sputum were twofold higher in subjects with acute asthma with virus infection (317.5×104/ml) than in non‐asthmatic subjects with virus infection (165×104/ml).
The intuitive influence of RV infection on asthma would be its ability to induce an inflammatory response from infected BECs and influence recruitment of inflammatory cells to the airways. In vitro infection of cell lines and primary BECs shows that RV infection leads to the release of the pro‐inflammatory mediators IL‐6, IL‐8, TNF‐α, and IL‐1β33,35 as well as RANTES and granulocyte‐macrophage colony stimulating factor (GM‐CSF). Increased levels of RANTES32 and, more recently, the chemokine IP‐1036 have been shown to correlate with in vivo virus replication. In addition, at least in a cell line, RV induces the release of the eosinophil chemoattractant eotaxin.37 RANTES is a CC chemokine with important antiviral effects and the ability to recruit lymphocytes to the airways, while IL‐6 and IL‐8 play important roles in neutrophil trafficking. In addition, there is evidence that RV infection upregulates the intercellular adhesion molecule 1 (ICAM‐1)—incidentally the receptor for 90% of RV serotypes—which also plays a central role in the movement of inflammatory cells into the airways.38 These in vitro pro‐inflammatory effects have been confirmed in human studies in which volunteers infected with RV had increased levels of markers of eosinophilic activation, IL‐8, and neutrophilia,39,40 and infiltration of the airways with eosinophils, CD4 and CD8 lymphocytes.41 These findings are also reflected in the effect of these experimental infections on airway physiology in asthma with increases in bronchial hyperresponsiveness41 and a fall in forced expiratory volume in 1 second (FEV1).42 However, some experimental infection models have shown only modest inflammatory and physiological changes, raising concerns about how well these models reflect acute asthma40 and whether other factors in addition to RV may be needed to trigger an acute exacerbation.
The importance of the pro‐inflammatory effect of virus infection has been shown in a study of adults presenting to the ER with acute asthma in which airway inflammation was assessed by sputum induction.5 Those with virus induced asthma had distinct airway inflammation compared with those with non‐infective acute asthma, with raised sputum neutrophils, neutrophil elastase, and evidence of lower airway cell necrosis with increased levels of lactate dehydrogenase (LDH). Subjects had a lower FEV1 at presentation, which remained lower even a month later, and a longer stay in hospital. Of these inflammatory markers, LDH—potentially a measure of direct virus induced lower airway damage—was most strongly associated with the length of hospital admission for the asthma exacerbation.
These studies have also confirmed the importance of the viral induced chemokine response with increased RANTES gene expression seen as a feature of respiratory viral infection.25 An additional observation was the increase in airway gene expression for IL‐1025 which was seen in subjects with acute asthma with viral infection but not in non‐asthmatic subjects with viral infection. The anti‐eosinophilic effects of IL‐10 may explain the low eosinophil numbers in viral induced asthma, and suggest a role for T cell regulation in the acute events in asthma exacerbation.
An interaction between pre‐existing allergic sensitisation and inflammation may influence the pathogenesis of virus induced asthma ((tablestables 3 and 44).). In children, increased nasal eosinophilic inflammation and serum IgE increased the risk of wheezing with colds.23 While the inflammatory and physiological effects of experimental RV infection were enhanced in subjects with evidence of allergic sensitisation (higher IgE),43 the greatest increases in hospital admissions for asthma were seen in asthmatic subjects who were infected and both sensitised and exposed to allergen.44 Similarly, enhanced physiological and inflammatory responses to allergen were seen in experimental RV infections in allergic subjects.